Advancements In Pharmacotherapy for Hyperlipidemia: A Comprehensive Review of Recent Drug Innovations and Clinical Outcomes

Authors

Abstract

Hyperlipidemia, characterized by elevated blood lipid levels, significantly contributes to cardiovascular diseases (CVDs), the leading cause of global mortality per the World Health Organization (WHO). Studies reveal a 20-30% increase in coronary heart disease risk for every 1 mmol/L rise in LDL-C levels. While statins are widely used, novel pharmacotherapeutic approaches are necessary for effective hyperlipidemia management and CVD risk reduction. Recent clinical trials demonstrate the efficacy of innovative drugs like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in lowering LDL-C levels and reducing adverse cardiovascular events. These findings highlight the potential of new therapies to enhance existing treatments for hyperlipidemia. Additionally, safety evaluations of emerging lipid-lowering agents address concerns about adverse effects and long-term risks. Despite progress, challenges persist in refining treatment strategies and ensuring equitable access to advanced therapies, especially for marginalized populations. Incorporating innovative pharmacotherapies into current approaches offers personalized and efficient hyperlipidemia management. Continued research and interdisciplinary collaborations are vital for advancing our understanding of lipid metabolism and translating scientific discoveries into improved patient outcomes and cardiovascular health. Ongoing innovation and investment in tailored hyperlipidemia therapies are crucial for better outcomes in individuals at risk of CVDs.

Keywords: hyperlipidemia, pcsk9 inhibitors, bempedoic acid, evinacumab, inclisiran mipomersen, volanesorsen

Keywords:

hyperlipidemia, pcsk9 inhibitors, bempedoic acid, evinacumab, inclisiran mipomersen, volanesorsen

DOI

https://doi.org/10.22270/jddt.v14i4.6533

Author Biographies

Hrithik Dey, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Vatsala Agarwal, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

MD Naushad Ali, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Astha Upadhyay, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Sufia Shafieq, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Bhupender Dixit, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Sahil Tomar, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Mahewish Tarannum, Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

Lloyd Institute of Management and Technology, Plot No.-11, Knowledge Park-II, Greater Noida, Uttar Pradesh, India-201306

References

Mainieri F, La Bella S, Chiarelli F. Hyperlipidemia and Cardiovascular Risk in Children and Adolescents. Biomedicines. 2023 Mar 7;11(3):809. https://doi.org/10.3390/biomedicines11030809 PMid:36979789 PMCid:PMC10045454

Stewart J, McCallin T, Martinez J, Chacko S, Yusuf S. Hyperlipidemia. Pediatrics in review. 2020 Aug 1;41(8):393-402. https://doi.org/10.1542/pir.2019-0053 PMid:32737252

Nouh F, Omar M, Younis M. Risk factors and management of hyperlipidemia. Asian Journal of Cardiology Research. 2018 Dec 29;2(1):1-0. https://doi.org/10.9734/JCTI/2018/38880

Yao YS, Li TD, Zeng ZH. Mechanisms underlying direct actions of hyperlipidemia on myocardium: an updated review. Lipids in Health and Disease. 2020 Dec;19(1):1-6. https://doi.org/10.1186/s12944-019-1171-8 PMid:32035485 PMCid:PMC7007679

Shattat GF. A review article on hyperlipidemia: types, treatments and new drug targets. Biomedical and Pharmacology Journal. 2015 May 3;7(1):399-409. https://doi.org/10.13005/bpj/504

Abbate SL, Brunzell JD. Pathophysiology of hyperlipidemia in diabetes mellitus. Journal of cardiovascular pharmacology. 1990 Jan 1;16:S1-7. https://doi.org/10.1097/00005344-199006169-00002

Xu Y, Fu M. Alterations of HDL subclasses in hyperlipidemia. Clinica Chimica Acta. 2003 Jun 1;332(1-2):95-102. https://doi.org/10.1016/S0009-8981(03)00138-4 PMid:12763286

Nelson RH. Hyperlipidemia as a risk factor for cardiovascular disease. Primary Care: Clinics in Office Practice. 2013 Mar 1;40(1):195-211. https://doi.org/10.1016/j.pop.2012.11.003 PMid:23402469 PMCid:PMC3572442

Evans J, Rich E, Davies B, Allwood R. Education, disordered eating and obesity discourse: Fat fabrications. Routledge; 2008 Jun 6. https://doi.org/10.4324/9780203926710

Kones R. Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. Drug design, development and therapy. 2011 Jun 13:325-80. https://doi.org/10.2147/DDDT.S14934 PMid:21792295 PMCid:PMC3140289

Labarthe DR. Epidemiology and Prevention of Cardiovascular Diseases: A Global Challenge: A Global Challenge.

Weintraub WS, Daniels SR, Burke LE, Franklin BA, Goff Jr DC, Hayman LL, Lloyd-Jones D, Pandey DK, Sanchez EJ, Schram AP, Whitsel LP. Value of primordial and primary prevention for cardiovascular disease: a policy statement from the American Heart Association. Circulation. 2011 Aug 23;124(8):967-90. https://doi.org/10.1161/CIR.0b013e3182285a81 PMid:21788592

Brautbar A, Ballantyne CM. Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nature Reviews Cardiology. 2011 May;8(5):253-65. https://doi.org/10.1038/nrcardio.2011.2 PMid:21321561

Kones R. Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes. Vascular Health and Risk Management. 2013 Oct 21:617-70. https://doi.org/10.2147/VHRM.S37119 PMid:24174878 PMCid:PMC3808150

Bozkurt B, Aguilar D, Deswal A, Dunbar SB, Francis GS, Horwich T, Jessup M, Kosiborod M, Pritchett AM, Ramasubbu K, Rosendorff C. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation. 2016 Dec 6;134(23):e535-78. https://doi.org/10.1161/CIR.0000000000000450

Hu JQ, Yan YH, Xie H, Feng XB, Ge WH, Zhou H, Yu LL, Sun LY, Xie Y. Targeting abnormal lipid metabolism of T cells for systemic lupus erythematosus treatment. Biomedicine & Pharmacotherapy. 2023 Sep 1;165:115198. https://doi.org/10.1016/j.biopha.2023.115198 PMid:37536033

Saceleanu VM, Toader C, Ples H, Covache-Busuioc RA, Costin HP, Bratu BG, Dumitrascu DI, Bordeianu A, Corlatescu AD, Ciurea AV. Integrative approaches in acute ischemic stroke: from symptom recognition to future innovations. Biomedicines. 2023 Sep 23;11(10):2617. https://doi.org/10.3390/biomedicines11102617 PMid:37892991 PMCid:PMC10604797

Onwe P, Folawiyo M, Anyigor-Ogah CS, Umahi G, Okorocha AE, Afoke A. Hyperlipidemia: etiology and possible control. IOSR J Dent Med Sci. 2015;14(10):93-100.

Zhang D, Wei Y, Huang Q, Chen Y, Zeng K, Yang W, Chen J, Chen J. Important hormones regulating lipid metabolism. Molecules. 2022 Oct 19;27(20):7052. https://doi.org/10.3390/molecules27207052 PMid:36296646 PMCid:PMC9607181

Havel RJ. Lipid transport function of lipoproteins in blood plasma. American Journal of Physiology-Endocrinology and Metabolism. 1987 Jul 1;253(1):E1-5. https://doi.org/10.1152/ajpendo.1987.253.1.E1 PMid:3037916

Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Advances in physiology education. 2004 Sep;28(3):105-6. https://doi.org/10.1152/advan.00048.2003

PMid:15319192

Aikawa M, Libby P. The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovascular pathology. 2004 May 1;13(3):125-38. https://doi.org/10.1016/S1054-8807(04)00004-3 PMid:15081469

Daniels TF, Killinger KM, Michal JJ, Wright Jr RW, Jiang Z. Lipoproteins, cholesterol homeostasis and cardiac health. International journal of biological sciences. 2009;5(5):474. https://doi.org/10.7150/ijbs.5.474 PMid:19584955 PMCid:PMC2706428

Gianazza E, Brioschi M, Martinez Fernandez A, Casalnuovo F, Altomare A, Aldini G, Banfi C. Lipid peroxidation in atherosclerotic cardiovascular diseases. Antioxidants & redox signaling. 2021 Jan 1;34(1):49-98. https://doi.org/10.1089/ars.2019.7955 PMid:32640910

Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clinical biochemistry. 2009 Sep 1;42(13-14):1331-46. https://doi.org/10.1016/j.clinbiochem.2009.05.018 PMid:19501581

Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. International journal of molecular sciences. 2014 Apr 11;15(4):6184-223. https://doi.org/10.3390/ijms15046184 PMid:24733068 PMCid:PMC4013623

LaRosa JC, Deedwania PC, Shepherd J, Wenger NK, Greten H, DeMicco DA, Breazna A, TNT Investigators. Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial). The American journal of cardiology. 2010 Feb 1;105(3):283-7. https://doi.org/10.1016/j.amjcard.2009.09.025 PMid:20102935

Gibson CM, Pride YB, Hochberg CP, Sloan S, Sabatine MS, Cannon CP, TIMI Study Group. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome: PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Substudy. Journal of the American College of Cardiology. 2009 Dec 8;54(24):2290-5. https://doi.org/10.1016/j.jacc.2009.09.010 PMid:19958964

Qamar A, Giugliano RP, Bohula EA, Park JG, Jarolim P, Murphy SA, Blazing MA, Califf RM, Cannon CP, Braunwald E, Morrow DA. Biomarkers and clinical cardiovascular outcomes with ezetimibe in the IMPROVE-IT trial. Journal of the American College of Cardiology. 2019 Aug 27;74(8):1057-68. https://doi.org/10.1016/j.jacc.2019.06.038 PMid:31439215

Sharp Collaborative Group. Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. American heart journal. 2010 Nov 1;160(5):785-94. https://doi.org/10.1016/j.ahj.2010.08.012 PMid:21095263

Steg PG, Szarek M, Bhatt DL, Bittner VA, Bregeault MF, Dalby AJ, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA. Effect of alirocumab on mortality after acute coronary syndromes: an analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation. 2019 Jul 9;140(2):103-12. https://doi.org/10.1161/CIRCULATIONAHA.118.038840 PMid:31117810 PMCid:PMC6661243

Goldberg AC, Leiter LA, Stroes ES, Baum SJ, Hanselman JC, Bloedon LT, Lalwani ND, Patel PM, Zhao X, Duell PB. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial. Jama. 2019 Nov 12;322(18):1780-8. https://doi.org/10.1001/jama.2019.16585 PMid:31714986 PMCid:PMC6865290

Nicholls S, Lincoff AM, Bays HE, Cho L, Grobbee DE, Kastelein JJ, Libby P, Moriarty PM, Plutzky J, Ray KK, Thompson PD. Rationale and design of the CLEAR-outcomes trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance. American heart journal. 2021 May 1;235:104-12. https://doi.org/10.1016/j.ahj.2020.10.060 PMid:33470195

Yu RZ, Geary RS, Flaim JA, Riley GC, Tribble DL, vanvliet AA, Wedel MK. Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2′--O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe. Clinical pharmacokinetics. 2009 Jan;48:39-50. https://doi.org/10.2165/0003088-200948010-00003 PMid:19071883

Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, Hesson LA, Osei SY, Kaplan R, Stunkard AJ. Randomized trial of lifestyle modification and pharmacotherapy for obesity. New England Journal of Medicine. 2005 Nov 17;353(20):2111-20. https://doi.org/10.1056/NEJMoa050156 PMid:16291981

Becker DM, Allen JK. Improving compliance in your dyslipidemic patient: an evidence‐based approach. Journal of the American Academy of Nurse Practitioners. 2001 May;13(5):200-7. https://doi.org/10.1111/j.1745-7599.2001.tb00021.x PMid:11930470

Fatahi S, Daneshzad E, Kord-Varkaneh H, Bellissimo N, Brett NR, Azadbakht L. Impact of diets rich in whole grains and fruits and vegetables on cardiovascular risk factors in overweight and obese women: a randomized clinical feeding trial. Journal of the American College of Nutrition. 2018 Oct 3;37(7):568-77. https://doi.org/10.1080/07315724.2018.1444520 PMid:29702040

Cha D, Park Y. Association between dietary cholesterol and their food sources and risk for hypercholesterolemia: the 2012-2016 Korea national health and nutrition examination survey. Nutrients. 2019 Apr 15;11(4):846. https://doi.org/10.3390/nu11040846 PMid:30991629 PMCid:PMC6520795

Kokkinos P, Myers J. Exercise and physical activity: clinical outcomes and applications. Circulation. 2010 Oct 19;122(16):1637-48. https://doi.org/10.1161/CIRCULATIONAHA.110.948349 PMid:20956238

Shah J, Alsubaie AS, Sehar B, Khan FS, Omer EO, Almoajel AM, Zeb F. Association of Cigarette Smoking with Hyperlipidemia in Male Individuals. Food and Nutrition Sciences. 2021 Oct 11;12(10):937-49. https://doi.org/10.4236/fns.2021.1210069

Bruckert E, Ferrieres J. Evidence supporting primary prevention of cardiovascular diseases with statins: gaps between updated clinical results and actual practice. Archives of Cardiovascular Diseases. 2014 Mar 1;107(3):188-200. https://doi.org/10.1016/j.acvd.2014.01.011 PMid:24613429

McTaggart F, Jones P. Effects of statins on high-density lipoproteins: a potential contribution to cardiovascular benefit. Cardiovascular Drugs and therapy. 2008 Aug;22:321-38. https://doi.org/10.1007/s10557-008-6113-z PMid:18553127 PMCid:PMC2493531

Raschi E, Casula M, Cicero AF, Corsini A, Borghi C, Catapano A. Beyond statins: New pharmacological targets to decrease LDL-cholesterol and cardiovascular events. Pharmacology & therapeutics. 2023 Aug 9:108507. https://doi.org/10.1016/j.pharmthera.2023.108507 PMid:37567512

Norata GD, Tibolla G, Catapano AL. PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges. Vascular pharmacology. 2014 Aug 1;62(2):103-11. https://doi.org/10.1016/j.vph.2014.05.011 PMid:24924410

Tummala R, Gupta M, Devanabanda AR, Bandyopadhyay D, Aronow WS, Ray KK, Mamas M, Ghosh RK. Bempedoic acid and its role in contemporary management of hyperlipidemia in atherosclerosis. Annals of Medicine. 2022 Dec 31;54(1):1287-96.https://doi.org/10.1080/07853890.2022.2059559 PMid:35533049 PMCid:PMC9090378

Ruscica M, Sirtori CR, Carugo S, Banach M, Corsini A. Bempedoic acid: For whom and when. Current Atherosclerosis Reports. 2022 Oct;24(10):791-801. https://doi.org/10.1007/s11883-022-01054-2 PMid:35900636 PMCid:PMC9474414

Goyal A, Changez MI, Tariq MD, Mushtaq F, Shamim U, Sohail AH, Mahalwar G. Efficacy and Outcomes of Bempedoic Acid Versus Placebo in Patients with Statin-Intolerance: A Pilot Systematic Review and Meta-analysis of Randomized Controlled Trials. Current Problems in Cardiology. 2023 Dec 1:102236. https://doi.org/10.1016/j.cpcardiol.2023.102236 PMid:38043880

Laufs U, Banach M, Mancini GJ, Gaudet D, Bloedon LT, Sterling LR, Kelly S, Stroes ES. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. Journal of the American Heart Association. 2019 Apr 2;8(7):e011662. https://doi.org/10.1161/JAHA.118.011662 PMid:30922146 PMCid:PMC6509724

Hegele RA, Tsimikas S. Lipid-lowering agents: targets beyond PCSK9. Circulation research. 2019 Feb 1;124(3):386-404. https://doi.org/10.1161/CIRCRESAHA.118.313171 PMid:30702996

Lin Y, Parco C, Karathanos A, Krieger T, Schulze V, Chernyak N, Icks A, Kelm M, Brockmeyer M, Wolff G. Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis. BMJ open. 2022 Feb 1;12(2):e048893. https://doi.org/10.1136/bmjopen-2021-048893 PMid:35210334 PMCid:PMC8883220

Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJ, Thompson PD, Libby P, Cho L, Plutzky J, Bays HE. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. New England Journal of Medicine. 2023 Apr 13;388(15):1353-64. https://doi.org/10.1056/NEJMoa2215024 PMid:36876740

Ray KK, Nicholls SJ, Li N, Louie MJ, Brennan D, Lincoff AM, Nissen SE. Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial. The Lancet Diabetes & Endocrinology. 2024 Jan 1;12(1):19-28. https://doi.org/10.1016/S2213-8587(23)00316-9 PMid:38061370

Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. New England Journal of Medicine. 2019 Mar 14;380(11):1022-32. https://doi.org/10.1056/NEJMoa1803917 PMid:30865796

Ballantyne CM, Bays H, Catapano AL, Goldberg A, Ray KK, Saseen JJ. Role of bempedoic acid in clinical practice. Cardiovascular Drugs and Therapy. 2021 Aug;35(4):853-64. https://doi.org/10.1007/s10557-021-07147-5 PMid:33818688 PMCid:PMC8266788

Susekov AV, Korol LA, Watts GF. Bempedoic acid in the treatment of patients with dyslipidemias and statin intolerance. Cardiovascular drugs and therapy. 2021 Aug;35:841-52. https://doi.org/10.1007/s10557-020-07139-x PMid:33502687

Ballantyne CM, Banach M, Bays HE, Catapano AL, Laufs U, Stroes ES, Robinson P, Lei L, Ray KK. Long-term safety and efficacy of bempedoic acid in patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study). The American Journal of Cardiology. 2022 Jul 1;174:1-1. https://doi.org/10.1016/j.amjcard.2022.03.020 PMid:35483979

Biolo G, Vinci P, Mangogna A, Landolfo M, Schincariol P, Fiotti N, Mearelli F, Di Girolamo FG. Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome. Frontiers in Cardiovascular Medicine. 2022 Oct 28;9:1028355. https://doi.org/10.3389/fcvm.2022.1028355 PMid:36386319 PMCid:PMC9650075

Scherer DJ, Nelson AJ, Psaltis PJ, Nicholls SJ. Targeting low‐density lipoprotein cholesterol with PCSK9 inhibitors. Internal medicine journal. 2017 Aug;47(8):856-65. https://doi.org/10.1111/imj.13451 PMid:28401639

Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field?. Journal of the American College of Cardiology. 2015 Jun 23;65(24):2638-51. https://doi.org/10.1016/j.jacc.2015.05.001 PMid:26088304

Latimer J, Batty JA, Neely RD, Kunadian V. PCSK9 inhibitors in the prevention of cardiovascular disease. Journal of thrombosis and thrombolysis. 2016 Oct;42:405-19. https://doi.org/10.1007/s11239-016-1364-1 PMid:27095708 PMCid:PMC5010583

Cordero A, Rodríguez-Mañero M, Fácila L, Fernández-Olmo MR, Gómez-Martínez MJ, Valle A, Castellano JM, Toro MM, Seijas-Amigo J, Vicedo A, González-Juanatey JR. Prevention of myocardial infarction and stroke with PCSK9 inhibitors treatment: a metanalysis of recent randomized clinical trials. Journal of Diabetes & Metabolic Disorders. 2020 Dec;19:759-65. https://doi.org/10.1007/s40200-020-00557-6 PMid:33520801 PMCid:PMC7843775

Schwartz GG, Giugliano RP. Proprotein convertase subtilisin/kexin type 9 inhibition after acute coronary syndrome or prior myocardial infarction. Current Opinion in Lipidology. 2022 Jun 1;33(3):147-59. https://doi.org/10.1097/MOL.0000000000000830 PMid:35695614

Szarek M, White HD, Schwartz GG, Alings M, Bhatt DL, Bittner VA, Chiang CE, Diaz R, Edelberg JM, Goodman SG, Hanotin C. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial. Journal of the American College of Cardiology. 2019 Feb 5;73(4):387-96. https://doi.org/10.1016/j.jacc.2018.10.039 PMid:30428396

Filippatos TD, Kei A, Rizos CV, Elisaf MS. Effects of PCSK9 inhibitors on other than low-density lipoprotein cholesterol lipid variables. Journal of cardiovascular pharmacology and therapeutics. 2018 Jan;23(1):3-12. https://doi.org/10.1177/1074248417724868 PMid:28826253

Stoekenbroek RM, Hartgers ML, Rutte R, de Wijer DD, Stroes ES, Hovingh GK. PCSK9 inhibitors in clinical practice: delivering on the promise?. Atherosclerosis. 2018 Mar 1;270:205-10. https://doi.org/10.1016/j.atherosclerosis.2017.11.027 PMid:29254691

Gürgöze MT, Muller‐Hansma AH, Schreuder MM, Galema‐Boers AM, Boersma E, Roeters van Lennep JE. Adverse events associated with PCSK 9 inhibitors: a real‐world experience. Clinical Pharmacology & Therapeutics. 2019 Feb;105(2):496-504. https://doi.org/10.1002/cpt.1193 PMid:30053327 PMCid:PMC6704355

Lee EY, Yoon KH. How to interpret recent CV outcome trials and future: PCSK9 inhibitors. Journal of Lipid and Atherosclerosis. 2018 Jan 1;7(1):1-1. https://doi.org/10.12997/jla.2018.7.1.1

Mark DB, Schulman KA. PCSK9 inhibitors and the choice between innovation, efficiency, and affordability. Jama. 2017 Aug 22;318(8):711-2. https://doi.org/10.1001/jama.2017.8907 PMid:28829851

Bagepally BS, Sasidharan A. Incremental net benefit of lipid-lowering therapy with PCSK9 inhibitors: a systematic review and meta-analysis of cost-utility studies. European Journal of Clinical Pharmacology. 2021 Oct 27:1-3. https://doi.org/10.31219/osf.io/mw8y4

Hess CN, Low Wang CC, Hiatt WR. PCSK9 inhibitors: mechanisms of action, metabolic effects, and clinical outcomes. Annual review of medicine. 2018 Jan 29;69:133-45. https://doi.org/10.1146/annurev-med-042716-091351 PMid:29095667

Ahmad Z, Banerjee P, Hamon S, Chan KC, Bouzelmat A, Sasiela WJ, Pordy R, Mellis S, Dansky H, Gipe DA, Dunbar RL. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation. 2019 Aug 6;140(6):470-86. https://doi.org/10.1161/CIRCULATIONAHA.118.039107 PMid:31242752 PMCid:PMC6686956

Pirillo A, Catapano AL. Evinacumab: A new option in the treatment of homozygous familial hypercholesterolemia. Expert Opinion on Biological Therapy. 2022 Jul 3;22(7):813-20. https://doi.org/10.1080/14712598.2022.2090242 PMid:35698895

Nurmohamed NS, Dallinga-Thie GM, Stroes ES. Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia. Expert review of cardiovascular therapy. 2020 Jun 2;18(6):355-61. https://doi.org/10.1080/14779072.2020.1768848 PMid:32511037

Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. European heart journal. 2020 Jan 1;41(1):99-109c. https://doi.org/10.1093/eurheartj/ehz785 PMid:31764986 PMCid:PMC6938588

Fiorentino R, Chiarelli F. Treatment of dyslipidaemia in children. Biomedicines. 2021 Aug 24;9(9):1078. https://doi.org/10.3390/biomedicines9091078 PMid:34572264 PMCid:PMC8470054

Kuehn BM. Evinacumab approval adds a new option for homozygous familial hypercholesterolemia with a hefty price tag. Circulation. 2021 Jun 22;143(25):2494-6. https://doi.org/10.1161/CIRCULATIONAHA.121.055463 PMid:34152800

Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJ, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N. Evinacumab for homozygous familial hypercholesterolemia. New England Journal of Medicine. 2020 Aug 20;383(8):711-20. https://doi.org/10.1056/NEJMoa2004215 PMid:32813947

Gaine SP, Quispe R, Patel J, Michos ED. New Strategies for Lowering Low-Density Lipoprotein Cholesterol for Cardiovascular Disease Prevention. Current Cardiovascular Risk Reports. 2022 Sep;16(9):69-78. https://doi.org/10.1007/s12170-022-00694-y PMid:36213094 PMCid:PMC9543364

Bashir B, Ho JH, Downie P, Hamilton P, Ferns G, Datta D, Cegla J, Wierzbicki AS, Dawson C, Jenkinson F, Delaney H. Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options. Metabolites. 2023 Apr 30;13(5):621. https://doi.org/10.3390/metabo13050621 PMid:37233662 PMCid:PMC10224445

Rizvi AA, Popovic DS, Papanas N, Pantea Stoian A, Al Mahmeed W, Sahebkar A, Janez A, Rizzo M. Current and emerging drugs for the treatment of atherosclerosis: The evidence to date. Expert Review of Cardiovascular Therapy. 2022 Jul 3;20(7):515-27. https://doi.org/10.1080/14779072.2022.2094771 PMid:35786159

Harada-Shiba M, Ali S, Gipe DA, Gasparino E, Son V, Zhang Y, Pordy R, Catapano AL. A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis. 2020 Dec 1;314:33-40. https://doi.org/10.1016/j.atherosclerosis.2020.10.013 PMid:33130482

Patel N, Parmar M, Patel P. Evinacumab.

Shamsudeen I, Hegele RA. Safety and efficacy of therapies for chylomicronemia. Expert Review of Clinical Pharmacology. 2022 Apr 3;15(4):395-405. https://doi.org/10.1080/17512433.2022.2094768 PMid:35762447

Kayki-Mutlu G, Aksoyalp ZS, Wojnowski L, Michel MC. A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021. Naunyn-schmiedeberg's Archives of Pharmacology. 2022 Aug;395(8):867-85. https://doi.org/10.1007/s00210-022-02250-2 PMid:35543739 PMCid:PMC9091141

Krzemińska J, Młynarska E, Radzioch E, Wronka M, Rysz J, Franczyk B. Management of Familial Hypercholesterolemia with Special Emphasis on Evinacumab. Biomedicines. 2022 Dec 16;10(12):3273. https://doi.org/10.3390/biomedicines10123273 Mid:36552028 PMCid:PMC9775211

Khoury E, Croteau L, Lauzière A, Gaudet D. Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia. Future Cardiology. 2022 Mar;18(6):507-18. https://doi.org/10.2217/fca-2021-0149 PMid:35469449

Sosnowska B, Adach W, Surma S, Rosenson RS, Banach M. Evinacumab, an ANGPTL3 Inhibitor, in the Treatment of Dyslipidemia. Journal of Clinical Medicine. 2022 Dec 25;12(1):168. https://doi.org/10.3390/jcm12010168 PMid:36614969 PMCid:PMC9821629

Ebenezer O, Comoglio P, Wong GK, Tuszynski JA. Development of Novel siRNA Therapeutics: A Review with a Focus on Inclisiran for the Treatment of Hypercholesterolemia. International Journal of Molecular Sciences. 2023 Feb 16;24(4):4019. https://doi.org/10.3390/ijms24044019 PMid:36835426 PMCid:PMC9966809

Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RP, Turner T, Visseren FL, Wijngaard P. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New England Journal of Medicine. 2017 Apr 13;376(15):1430-40. https://doi.org/10.1056/NEJMoa1615758 PMid:28306389

Ray KK, Stoekenbroek RM, Kallend D, Nishikido T, Leiter LA, Landmesser U, Wright RS, Wijngaard PL, Kastelein JJ. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA cardiology. 2019 Nov 1;4(11):1067-75. https://doi.org/10.1001/jamacardio.2019.3502 PMid:31553410 PMCid:PMC6763983

Ray KK, Troquay RP, Visseren FL, Leiter LA, Wright RS, Vikarunnessa S, Talloczy Z, Zang X, Maheux P, Lesogor A, Landmesser U. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): Results from the 4-year open-label extension of the ORION-1 trial. The Lancet Diabetes & Endocrinology. 2023 Feb 1;11(2):109-19. https://doi.org/10.1016/S2213-8587(22)00353-9 PMid:36620965

Wright RS, Koenig W, Landmesser U, Leiter LA, Raal FJ, Schwartz GG, Lesogor A, Maheux P, Stratz C, Zang X, Ray KK. Safety and tolerability of inclisiran for treatment of hypercholesterolemia in 7 clinical trials. Journal of the American College of Cardiology. 2023 Dec 12;82(24):2251-61. https://doi.org/10.1016/j.jacc.2023.10.007 PMid:38057066

Strilchuk L, Fogacci F, Cicero AF. Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data. Expert opinion on drug safety. 2019 Jul 3;18(7):611-21. https://doi.org/10.1080/14740338.2019.1620730 PMid:31100030

Wołowiec Ł, Osiak J, Wołowiec A, Wijata A, Grześk E, Kozakiewicz M, Banach J, Nowaczyk A, Nowaczyk J, Grześk G. Inclisiran-Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9. Pharmaceutics. 2023 Jan 18;15(2):323. https://doi.org/10.3390/pharmaceutics15020323 PMid:36839644 PMCid:PMC9965021

Cowart K, Singleton J, Carris NW. Inclisiran for the treatment of hyperlipidemia and for atherosclerotic cardiovascular disease risk reduction: a narrative review. Clinical Therapeutics. 2023 Jul 12. https://doi.org/10.1016/j.clinthera.2023.06.011 PMid:37451914

Kosmas CE, Muñoz Estrella A, Sourlas A, Silverio D, Hilario E, Montan PD, Guzman E. Inclisiran: a new promising agent in the management of hypercholesterolemia. Diseases. 2018 Jul 13;6(3):63. https://doi.org/10.3390/diseases6030063 PMid:30011788 PMCid:PMC6163360

Ray KK, Raal FJ, Kallend DG, Jaros MJ, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Lawrence D, Friedman A, Garcia Conde L. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. European Heart Journal. 2023 Jan 7;44(2):129-38. https://doi.org/10.1093/eurheartj/ehac594 PMid:36331326 PMCid:PMC9825807

Scicchitano P, Milo M, Mallamaci R, De Palo M, Caldarola P, Massari F, Gabrielli D, Colivicchi F, Ciccone MM. Inclisiran in lipid management: A Literature overview and future perspectives. Biomedicine & Pharmacotherapy. 2021 Nov 1;143:112227. https://doi.org/10.1016/j.biopha.2021.112227 PMid:34563953

Dyrbuś K, Gąsior M, Penson P, Ray KK, Banach M. Inclisiran-new hope in the management of lipid disorders?. Journal of Clinical Lipidology. 2020 Jan 1;14(1):16-27. https://doi.org/10.1016/j.jacl.2019.11.001 PMid:31879073

Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotides for the treatment of dyslipidaemia. European heart journal. 2012 Jun 1;33(12):1451-8. https://doi.org/10.1093/eurheartj/ehs084 PMid:22634577

Reiner Ž. Management of patients with familial hypercholesterolaemia. Nature Reviews Cardiology. 2015 Oct;12(10):565-75. https://doi.org/10.1038/nrcardio.2015.92 PMid:26076948

Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014 Mar 4;129(9):1022-32. https://doi.org/10.1161/CIRCULATIONAHA.113.001292 PMid:24589695

Panta R, Dahal K, Kunwar S. Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. Journal of clinical lipidology. 2015 Mar 1;9(2):217-25. https://doi.org/10.1016/j.jacl.2014.12.006 PMid:25911078

Fogacci F, Ferri N, Toth PP, Ruscica M, Corsini A, Cicero AF. Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials. Drugs. 2019 May 1;79:751-66. https://doi.org/10.1007/s40265-019-01114-z PMid:30989634

Larsen LE, Stoekenbroek RM, Kastelein JJ, Holleboom AG. Moving targets: recent advances in lipid-lowering therapies. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019 Mar;39(3):349-59. https://doi.org/10.1161/ATVBAHA.118.312028 PMid:30676072

Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJ. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. Journal of clinical lipidology. 2016 Jul 1;10(4):1011-21. https://doi.org/10.1016/j.jacl.2016.04.013 PMid:27578134

Laina A, Gatsiou A, Georgiopoulos G, Stamatelopoulos K, Stellos K. RNA therapeutics in cardiovascular precision medicine. Frontiers in Physiology. 2018 Jul 25;9:953. https://doi.org/10.3389/fphys.2018.00953 PMid:30090066 PMCid:PMC6068259

Swastini DA, Wiryanthini IA, Ariastuti NL, Muliantara A. Atherosclerosis prediction with high sensitivity C-reactive protein (hs-CRP) and related risk factor in patient with dyslipidemia. Open access Macedonian journal of medical sciences. 2019 Nov 11;7(22):3887. https://doi.org/10.3889/oamjms.2019.526 PMid:32127998 PMCid:PMC7048367

Alhamadani F, Zhang K, Parikh R, Wu H, Rasmussen TP, Bahal R, Zhong XB, Manautou JE. Adverse Drug Reactions and Toxicity of the Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. Drug Metabolism and Disposition. 2022 Jun 1;50(6):879-87. https://doi.org/10.1124/dmd.121.000418 PMid:35221289

Parham JS, Goldberg AC. Mipomersen and its use in familial hypercholesterolemia. Expert opinion on pharmacotherapy. 2019 Jan 22;20(2):127-31. https://doi.org/10.1080/14656566.2018.1550071 PMid:30526168 PMCid:PMC6438693

Geary RS, Baker BF, Crooke ST. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (Kynamro®): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clinical pharmacokinetics. 2015 Feb;54:133-46. https://doi.org/10.1007/s40262-014-0224-4 PMid:25559341 PMCid:PMC4305106

Arca M, Hsieh A, Soran H, Rosenblit P, O'Dea L, Stevenson M. The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study. Expert Review of Cardiovascular Therapy. 2018 Jul 3;16(7):537-46. https://doi.org/10.1080/14779072.2018.1487290 PMid:29889589

Santamarina-Fojo S. The familial chylomicronemia syndrome. Endocrinology and metabolism clinics of North America. 1998 Sep 1;27(3):551-67. https://doi.org/10.1016/S0889-8529(05)70025-6 PMid:9785052

D'erasmo L, Gallo A, Di Costanzo A, Bruckert E, Arca M. Evaluation of efficacy and safety of antisense inhibition of apolipoprotein C-III with volanesorsen in patients with severe hypertriglyceridemia. Expert Opinion on Pharmacotherapy. 2020 Sep 21;21(14):1675-84. https://doi.org/10.1080/14656566.2020.1787380 PMid:32646313

Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O'Dea LS, Stroes ES. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. The lancet Diabetes & endocrinology. 2021 May 1;9(5):264-75.

Davidson MH, Benes L, Wierzbicki AS. Fast Facts: Familial Chylomicronemia Syndrome: Raising awareness of a rare genetic disease. Karger Medical and Scientific Publishers; 2021 Nov 30. https://doi.org/10.1159/isbn.978-3-318-06985-3

Witztum JL, Gaudet D, Arca M, Jones A, Soran H, Gouni-Berthold I, Stroes ES, Alexander VJ, Jones R, Watts L, Xia S. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome: Long-term efficacy and safety data from patients in an open-label extension trial. Journal of Clinical Lipidology. 2023 May 1;17(3):342-55. https://doi.org/10.1016/j.jacl.2023.03.007 PMid:37100699

Benes LB, Brandt EJ, Davidson MH. Advances in diagnosis and potential therapeutic options for familial chylomicronemia syndrome. Expert Opinion on Orphan Drugs. 2018 Feb 1;6(2):141-9. https://doi.org/10.1080/21678707.2018.1419863

Lightbourne M, Startzell M, Bruce KD, Brite B, Muniyappa R, Skarulis M, Shamburek R, Gharib AM, Ouwerkerk R, Walter M, Eckel RH. Volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, increases lipoprotein lipase activity and lowers triglycerides in partial lipodystrophy. Journal of Clinical Lipidology. 2022 Nov 1;16(6):850-62. https://doi.org/10.1016/j.jacl.2022.06.011 PMid:36195542 PMCid:PMC9771980

Lu Y, Cui X, Zhang L, Wang X, Xu Y, Qin Z, Liu G, Wang Q, Tian K, Lim KS, Charles CJ. The functional role of lipoproteins in atherosclerosis: Novel directions for diagnosis and targeting therapy. Aging and Disease. 2022 Apr;13(2):491. https://doi.org/10.14336/AD.2021.0929 PMid:35371605 PMCid:PMC8947823

Li Z, Zhao P, Zhang Y, Wang J, Wang C, Liu Y, Yang G, Yuan L. Exosome-based Ldlr gene therapy for familial hypercholesterolemia in a mouse model. Theranostics. 2021;11(6):2953. https://doi.org/10.7150/thno.49874 PMid:33456582 PMCid:PMC7806494

Zhao H, Li Y, He L, Pu W, Yu W, Li Y, Wu YT, Xu C, Wei Y, Ding Q, Song BL. In vivo AAV-CRISPR/Cas9-mediated gene editing ameliorates atherosclerosis in familial hypercholesterolemia. Circulation. 2020 Jan 7;141(1):67-79. https://doi.org/10.1161/CIRCULATIONAHA.119.042476 PMid:31779484

Chen SJ, Rader DJ, Tazelaar J, Kawashiri MA, Gao GP, Wilson JM. Prolonged correction of hyperlipidemia in mice with familial hypercholesterolemia using an adeno-associated viral vector expressing very-low-density lipoprotein receptor. Molecular Therapy. 2000 Sep 1;2(3):256-61. https://doi.org/10.1006/mthe.2000.0122 PMid:10985956

Preta G. Development of New Genome Editing Tools for the Treatment of Hyperlipidemia. Cells. 2023 Oct 16;12(20):2466. https://doi.org/10.3390/cells12202466 PMid:37887310 PMCid:PMC10605581

Gareri C, Polimeni A, Giordano S, Tammè L, Curcio A, Indolfi C. Antisense oligonucleotides and small interfering RNA for the treatment of dyslipidemias. Journal of Clinical Medicine. 2022 Jul 4;11(13):3884. https://doi.org/10.3390/jcm11133884 PMid:35807171 PMCid:PMC9267663

Jiang L, Wang LY, Cheng XS. Novel approaches for the treatment of familial hypercholesterolemia: current status and future challenges. Journal of Atherosclerosis and Thrombosis. 2018 Aug 1;25(8):665-73. https://doi.org/10.5551/jat.43372 PMid:29899171 PMCid:PMC6099065

Duffy D, Rader DJ. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation. 2006 Feb 28;113(8):1140-50. https://doi.org/10.1161/CIRCULATIONAHA.105.593855 PMid:16505192

G Athyros V, Tziomalos K, Karagiannis A, P Mikhailidis D. Hypolipidaemic drug treatment: yesterday is not gone yet, today is challenging and tomorrow is coming soon; let us combine them all. Current Pharmaceutical Design. 2014 Dec 1;20(40):6350-7. https://doi.org/10.2174/1381612820666140620154545 PMid:24953393

Mathur M, Kusum Devi V. Potential of novel drug delivery strategies for the treatment of hyperlipidemia. Journal of drug targeting. 2016 Nov 25;24(10):916-26. https://doi.org/10.3109/1061186X.2016.1172586 PMid:27029893

Graham I, Shear C, De Graeff P, Boulton C, Catapano AL, Stough WG, Carlsson SC, De Backer G, Emmerich J, Greenfeder S, Kim AM. New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk. European Heart Journal-Cardiovascular Pharmacotherapy. 2018 Apr 1;4(2):119-27. https://doi.org/10.1093/ehjcvp/pvx031 PMid:29194462

Kadowaki T, Haneda M, Ito H, Sasaki K, Matsukawa M, Yamada Y. Long-term, real-world safety and efficacy of teneligliptin: a post-marketing surveillance of more than 10,000 patients with type 2 diabetes in Japan. Advances in Therapy. 2020 Mar;37:1065-86. https://doi.org/10.1007/s12325-019-01189-w PMid:31873865 PMCid:PMC7089720

Lytsy P, Westerling R. Patient expectations on lipid-lowering drugs. Patient education and counseling. 2007 Jul 1;67(1-2):143-50. https://doi.org/10.1016/j.pec.2007.03.004 PMid:17433602

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Dey H, Agarwal V, Ali MN, Upadhyay A, Shafieq S, Dixit B, et al. Advancements In Pharmacotherapy for Hyperlipidemia: A Comprehensive Review of Recent Drug Innovations and Clinical Outcomes. J. Drug Delivery Ther. [Internet]. 2024 Apr. 15 [cited 2025 Feb. 13];14(4):111-22. Available from: https://jddtonline.info/index.php/jddt/article/view/6533

How to Cite

1.
Dey H, Agarwal V, Ali MN, Upadhyay A, Shafieq S, Dixit B, et al. Advancements In Pharmacotherapy for Hyperlipidemia: A Comprehensive Review of Recent Drug Innovations and Clinical Outcomes. J. Drug Delivery Ther. [Internet]. 2024 Apr. 15 [cited 2025 Feb. 13];14(4):111-22. Available from: https://jddtonline.info/index.php/jddt/article/view/6533